21-fluoro-17-oxygenated-pregnane derivatives



United :itates Patent Qfiice 3,069,437 Patented Dec. 18, 1962 3,069,437 21-FLUORG-17-OXYGENATED-PREGNANE DERIVATIVES Raymond L. Peder-son, Kalamazoo, and John C. Bahcock,

Portage Township, Kalamazoo, Mich, assignors to The Upjohn Company, Kaiamazoo, Mich, a corporation of Michigan No Drawing. Filed May 15, 1953, Ser. No. 735,380 2 Claims. (61. 260-39745) This invention relates to novel 21-fluorinated steroids, and has among its objects the provision of the novel 21- fiuorinated compounds, 2l-fluoro-l7a-hydroxyprogesterone, 9( 11)-dehydro-21-fiuoro 17oz hydroxyprogesterone and their Not-acylates and 3,l7u-diacylates. Other objects will be apparent to those skilled in the art to which this invention pertains.

The novel 2l-fiuoro-l7a-hydroxyprogesterone, 9(ll)- dehydro-Zl-fiuoro-l7oc-hydroxyprogester0ne and their 170:- acylates and 3,17a-diacylates possess a high order of physiological activity, particularly oral and parenteral progestational activity. In addition they have marked antiinflammatory, central nervous system depressing, water and mineral regulating and anabolic and anti-estrogenic activity. The 9(1l)-dehydro compounds are especially useful as progestational agents being ten to twenty times as active as progesterone, and they are active when administered orally or parenterally.

These compounds affect the secretion of gonadotropins and thus regulate ovulation and endometrial and placental development and, particularly when used in conjunction with estrogens, e.g., ethinylestradiol and/or androgens, e.g., Halotestin (9oz-fill0r0 11,8 hydroxy-l7- methyl-testosterone) reduce fertility, and constitute effec tive therapy for dysmenorrhea, amenorrhea, endometriosis, threatened abortion and related gynecological disorders.

Administration of the compounds of this invention can be in conventional dosage forms, such as pills, tablets, capsules, solutions, syrups or eliXirs for oral use, or in liquid forms which are adaptable to the natural and synthetic steroid hormones for injectable products.

According to the present invention, the novel 2l-fiuoro- 17a-hydroxyprogesterone (IVa) and its Hot-acylates (Va) and 3,17-diacylates (VIa) are prepared from the known 17a,21-dihydroxy-4-pregnene-3,ZO-dione (la). The starting steroid, l7ot,21-dihydroxy-4-pregnene-3,20-dione (Ia) is treated with an organic sulfonyl halide such as methanesulfonyl chloride to produce 1701,21-dihydroxy-4-pregnene- 3,20-dione ZI-methanesulfonate (Ila), which is then re acted with an alkali metal iodide, e.g., sodium iodide to give 2l-iodo-17a-hydroxy-4-pregnene-3,ZO-dione (IIla). Treatment of 2l-iodo-17u-hydroXy-4-pregnene-3,20-dione (Illa) with silver fluoride is productive of the novel 21- fluoro-l7a-hydroxy-4-pregnene-3,20-dione (IVa), which can be converted under esterification conditions by paratoluenesulfonic acid or concentrated sulfuric acid and an appropriate acid anhydride to its Not-acylates (Va) and 3,17a-diacylates (VIa). For example, para-toluenesulfonic acid and acetic anhydride is productive of 21-fiuoro 17u-acetoxy-4-pregnene-3,ZO-dione and 21-fluoro-3,17adiacetoxy-3,5pregnadien-20-one.

In a similar series of reactions the novel 2l-fluoro-l7ahydroxy-4,9(ll)-pregnadiene-3,20-dione (IVb) and its Hoe-acylates (Vb) and 3,l7a-diacy lates (VIb) are prepared from l7a,2l-dihydroxy-4,9(1l)-pregnadiene-3,20- dione (lb). The starting steroid, l7ot,2l-dihydroxy-4,9 (ll)-pregnadiene-3,20-dione (Ib) is obtained by treating the known 17a,21-dihydroXy-4,9(ll)-pregnadiene-3,20- dione, ZI-acetate (compound 3 of US. Patent 2,640,838) with potassium bicarbonate. For example, by reacting 17a,21-dihydroxy-4,9(11)-pregnadiene 3,20 dione (lb) with methanesulfonyl chloride, l7a,2l-dihydroXy-4,9( l l pregnadiene-3,20-dione ZI-methanesulfonate (Ilb) is pro duced. Treatment of the thus-produced 17a,21-dihydroxy-4,9(1l)-pregnadiene-3,20-dione 21 methanesulfonate (Ilb) with sodium iodide results in the formation of 2l-iodo-l7ot-hydroxy 4,9(11) pregnadiene-3,20dione (1111:). Treatment of 21-iodo-l7a-hydroxy-4,9(11)-pregnadiene3,20-dione (1111;) with silver fluoride is productive of the novel 2l-fiuoro-17oz-hydroxy-4,9( l1)-pregnadiene-3,20-dione (IVb), which can be converted by esterification catalysts such as concentrated sulfuric acid or para-toluenesulfonic acid and an appropriate acid anhydride to its Not-acylates (Vb) and 3,l7u-diacylates (VIb). For example, para-toluenesulfonic acid and acetic anhydride is productive of 2l-fluoro-17a-acetoXy-4,9(l1)-pregnadiene-3,20-dione (Vb) and 2l-fiuoro-3,l7et-diacetoxy- 3,5,9(l1)-pregnatrien-20-one (Vlb).

The 17 acylates and 3,17 diacylates of this invention represented by Formulae V and VI of the reaction scheme shown below which are preferred are those wherein the acyl radical is that of a hydrocarbon carboxylic acid of from one to twelve carbon atoms, inclusive.

The products and process of the present invention are shown by the following formulae and more specifically by the examples.

CH3 CH3 onion r irnosonzn 0:0 0:0 CH3/\ I 0111A {n I(a,b) H01.

CH3 CH3 (llHaF CHiI 0:0 =0 0113A 0113/\ 1 i j l I 0: Q:

IV(a, b) III(a, 6)

CH: CH;

(EH2)? C'HrF 0:0 =0 --OAc '----0Ac i i j 0: AGO-V V (a, b) VIa, 0*)

wherein Ac is an acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, and X is a single or double bond.

The compounds of the instant invention, 21-fiuoro- 17u-hydroxyprogesterone, 9( 1 1 -dehydro-21-fluoro-17ahydroxyprogesterone and their 17a-acylates and 3,17a-diacylates, are useful as starting material for other physiologically important compounds. For example, 21-fluoro- 17a-hydroxyprogesterone can be converted microbiologically by Cunninghamella blakesleeana or Abfidia glauca to the lle-hydroxy derivative, 21-flu0ro-1l,8,17adihydroxy-4-pregnene-3,20-dione, which has marked glucocort'icoid activity. 9 1 1 -dehydro-21-fluoro-17a-hydroxyprogesterone can be converted through the 9,11- oxide by the method of Fried [see I. Am. Chem. Soc., 75, 2273 (1953) and 76, 1455 (1954)] to the 9oc-fl11010- 11/3-hydroxy derivative, 9a,2l-difillOr0 115,170: dihydroxy-4-pregnene-3,20-dione, which also has pronounced glucocorticoid activity. In addition the enol acetates, 2l-fiuoro-3,l7a-diacetoxy-3,S-pregnadien 20 one (Vi a) and 21-fluoro-3,17a-diacetoxy-3,5,9(11)-pregnatrien-20- one (VIb) can be selectively hydrolyzed by refluxing them with boron trifluoride in methanol, gaseous hydrogen chloride in ethanol or aqueous potassium hydroxide in methanol to produce 21-fluoro-17a-acetoXy-4-pregnene-3,20-dione (Va) and 21-fiuoro-17oc-acetoxy-4,9- (11)-pregnadiene-3,20-dione (Vb).

The following examples are illustrative of the products and processes of the present invention, but are not to be construed as limiting.

Example 1. 1704,21-Dihydrxy-4-Pregnene-3,20-Di0ne 21 -Methanesulf0nate (II a) (I 1 -Desoxy-1 7a-Hydr0xycarlicosterone 21 -Methan esulfonate) Twenty grams of 17a,21-dihydroxy-4-pregnen-3,20- dione (la) (the known 1l-desoxy-17a-hydroxycorticosterone) was dissolved in 100 milliliters of pyridine and cooled to about zero degrees centigrade and 6.8 milliliters of methanesulfonyl chloride was added to the solution. This was accompanied by a rapid temperature rise to about 25 degrees centigrade. After a period of two hours of continuous coo-ling in an ice-bath, the mixture was diluted with 600 milliliters of cold water at which point precipitation occurred. Filtration of the crude solid yielded 20.5 grams with a melting point of 172 to 176 degrees centigrade- Recrystallization from acetone gave an analytical sample of 17a,21-dihydroxy 4 pregnen-3,20-dione ZI-methanesulfonate (Ila) that melted at 183 to 185 degrees centigrade (decomposition).

Analysis.Calculated for C H O S: S, 7.55. Found: S, 7.37, 7.53.

Example 2.-21-10d0-17ot-Hydr0xy-4-Pregnen- 3,20-Di0ne (Illa) 18.5 grams of 17a,21-dihydroxy-4-pregnen-3,20-dione 21-methanesulfonate was dissolved in 260 milliliters of warm acetone. Nineteen grams of. sodium iodide dissolved in 165 milliliters of acetone was added with stirring to the solution of the steroid. The reaction mixture was warmed under reflux with stirring for a period of fifteen minutes, then 200 grams of ice was added, followed by the addition of two grams of sodium thiosulfate dissolved in 500 milliliters of water. The precipitated solid that formed wa filtered, washed with water and dried in vacuo at 25 degrees centigrade. The yield of 2l-iodo-17a-hydroxy-4-pregnen-3,20-dione was 16.4 grams. It melted at 122 to 126 degrees (decomposition).

Example 3.21-Flu0r0-17a-Hydr0xy-4-Pregnen- 3,20-Di0ne (IVa) 14.4 grams of 2l-iodo-17a-hydroxy-4-pregnen-3,20- dione (Illa) was dissolved in 1400 milliliters of acetonitrile and shielded from daylight. Four 7.5 milliliter portions of fifty percent aqueous silver fluoride were added to the steroid with stirring at twenty minute intervals. The reaction mixture was warmed to about forty degrees centigrade and stirred an additional period of two hours. The reaction mixture was filtered through 4 Celite (a diatom-aceous earth filter aid) and the filtrate concentrated to dryness over a water bath heated to fifty degrees centigrade.

The residue was extracted with four 300 milliliter portions of methylene chloride and the combined extracts dried over anhydrous sodium sulfate. Evaporation of the solvent yielded thirteen grams of crystalline solid. This material was dissolved in 600 milliliters of methylene chloride and adsorbed on a 400 gram column of Florisil (a synthetic magnesium silicate). It was eluted with a mixture of acetone in Skellysolve B (hexane hydrocarbons) using 400 milliliter fractions, as follows:

Fractions 1 to 4 9 percent acetone. Fractions 5 to 21 10 percent acetone. Fractions 22 to 40 12 percent acetone.

Fractions 11 to 35, inclusive, weighing a total of 4.51 grams, were combined and dissolved in 300 milliliters of methylene chloride and fifty milliliters of methyl ethyl ketone. about forty milliliters remained, then the solution was cooled and 3.5 grams of crystalline 2-fluoro-17a-hydroxy- 4-pregnen-3,20-dione (IVa) separated. It melted at 222 to 226 degrees centigrade and had a rotation of [oc] plus 132 degrees (in chloroform). The infrared absorption spectrum showed a maximum at 1725 centimeters- (mull) characteristic of a-halo ketones and the remainder of the spectrum supported this structure.

Analysis.--Calculated for C H FO C, 72.38; H, 8.39; F, 5.45. Found: C, 72.13; H, 8.42; F, 5.32.

The combined chromatographic fractions 4 and 5 weighed 1.46 grams. This material was crystallized from acetone to yield one gram of 17a,21-epoxy-4-pregnen- 3,20-dione with a melting point of 194 to 198 degrees centigrade, a rotation of [041 plus 216 degrees (in chloroform) and a negative Beilstein test for halogen. The infrared absorption spectrum showed the absence of hydroxyl absorption and the presence of a strained ring ketone absorption at 1805 centimeterr Analysis.Calculated for C H O C, 76.79; H, 8.59. Found: C, 76.04; H, 8.35.

This substance is a valuable diuretic agent and regulator of mineral metabolism and is accordingly useful in treating edema, and circulatory and cardiac conditions. It also exhibits gonadotropin inhibiting and central nervous system regulating activity.

Example 4 .21 -Fla0r -1 7a-A cez0xy-4-Pregnen-3,20-Dione (Va) (21 -Fla0ro-1 7 vc-H ydroxy progesterone 17-Acetate) and 21 -Flu0r0-3,1 7 a-D iacet0xy-3,5 -Pregnaa'ien- 2 O-one VI a) methylene chloride and adsorbed on a column of thirty grams of Florisil. Elution with forty milliliter portions of a mixture composed of ten percent of acetone and ninety percent of Skellysolve B hexanes yielded two products.

Fractions 4 and 5 weighed 172 milligrams'and were combined and crystallized from methylene chloride-Skellysolve B to give 78 milligrams of 2l-fiuoro-3,17a-diacetoxy-3,5- pregnadien-20-one (VIa) with a melting point of 164 to 166 degrees Centigrade. It has an infrared absorption spectrum consistent with this structure.

Analysis.-Calculated for C H FO C, 69.42; H, 7.69. Found: C, 69.51; H, 7.78.

Fractions 10 to 15, inclusive, of the above chromatogram were pooled and crystallized from methylene chloride-Skellysolve B hexanes to give 380 milligrams of 21- The solvent was evaporated until a volume of fiuoro-l7a-acetoxy-4-pregnene-3,20-dione (Va) with a melting point of 232 to 234 degrees centigrade and a rotation of [0:1 plus 57 degrees (in chloroform).

Analysis-Calculated for C H FO C, 70.74; H, 8.00; F, 4.87. Found: C, 70.83; H, 7.73; F, 4.76.

21-fluoro-17a-hydroxy-4-pregnene-3,20-dione is converted to other 21-fluoro-17a-acyloxy-4-pregnene-3,20-diones and 2l-fiuoro-3,17a-diacyloxy-3,5-pregnadien-20- ones by esterification of the 17u-hydroxyl and enol esterification of the 3-ketone by reaction with the appropriate acid, acid anhydride or acid halide in the presence of an acid catalyst such as paratoluenesulfonic acid or trifiuoroacetic anhydride. In the same manner as in Example 4 but instead of employing acetic anhydride, substituting such acid anhydrides as propionic, butyric, isobutyric, valeric, enanthic, caproic, caprylic, benzoic, cyclopentylpropionic, phenylacetic, phenylpropionic, trimethylacetic, t-butylacetic, cyclopentylcarboxylic, ethylbutyric, o-toluic, dodecanoic or cyclohexylacetic is productive of 2l-fluoro-17a-propionyloxy-4-pregnene-3,20-dione, 21-fiuoro-3,17a-dipropionyloxy-3,S-pregnadien-ZO-one, 2l-lluoro-l7a-butyryloxy-4-pregnene-3,20-dione, 2l-fluoro-3,l7a-dibutyryloxy-3,5-pregnadien-20-one, 2l-fluoro-17a-isobutyryloxy-4-pregnene-3,20-dione, 21-fiuoro-3,17a-diisobutyryloxy-3,S-pregnadien-ZO-one,

, 21-fiuoro-17a-valeryloxy-4-pregnene-3,20-dione,

2l-fiuoro-3,17a-divaleryloxy-3,5-pregnadien-20-one, Zl-fiuoro-17u-enanthoyloxy-4-pregnene-3,20-dione, 21-fiuoro-3,17wdienanthoyloxy-3,5-pregnadien-20-one, 2l-fiuoro-17a-caproyloxy-4-pregnene-3,20-dione, 21-fluoro-3,17a-dicaproyloxy-3,S-pregnadien-ZO-one, 2l-fluoro-l7u-capryloxy-4-pregnene-3,20-dione, 21-fluoro-3,17a-dicapryloxy-3,5-pregnadien-20-0ne, 21-fiuoro-17u-benzoyloxy-4-pregnene-3,20-dione, 2l-fluoro-3,17a-dibenzoyloxy-3,S-pregnadien-ZO-one, 21 fluoro 17a cyclopentylpropionyloxy 4 pregnene- 3,20-dione, 21 fluoro 3,17a dicyclopentylpropionyloxy 3,5 pregnadien-20-one, 21-fluor0-17a-phenylacetoxy-4-pregnene-3,20-dione, 2l-fiuoro-3,17u-diphenylacetoxy-3,S-pregnadien-ZO-one, 2l-fluoro-17a-phenylpropionyloxy-4-pregnene-3,20-dione, 21 fluoro 3,170 diphenylpropionyloxy 3,5 pregnadien-20-one, 2l-fiuoro-l7a-trimethylacetoxy-4-pregnene-3,20-dione, 21-fiuoro-3,17a-ditrirnethylacetoxy-3 ,5 -pregnadien-20-one, 2l-fluoro-17u-t-butylacetoxy-4-pregnene-3,20-dione, 21-flu0ro-3,17a-di-t-butylacetoxy-3,5-pregnadien-20-one, 21 fiuoro 17m cyclopentylcarboxyloxy 4 pregnene- 3,20-dione, 21 fluoro 3,170: dicyclopentylcarboxyloxy 3,5 pregnadien-ZO-one, 21-fiuoro-17a-ethylbutyryloxy-4-pregnene-3,20-dione, 21-fluoro-3,l7a-diethylbutyryloxy-3,S-pregnadien20-one, 21-fiuoro-17a-o-toluyloxy-4-pregnene3,20-dione, 2l-fluoro-3,17a-dio-toluyloxy-3,S-pregnadien-ZO-one, 21-fiuoro-17ot-decanoyloxy-4-pregnene-3,20-dione, 2l-fluoro-3,17a-didecanoyloxy-3,5-pregnadien-20-one, 21 fluoro 17a cyclohexylacetoxy 4 pregnene 3,20-

dione, and 21 fluoro 3,17 dicyclohexylacetoxy 3,5 pregnadien- 20-one,

respectively.

Example 5.--17a,21-Dihydr0xy-4,9 (11 -Prgnadiene- 3,20-Dione (lb) Twenty grams of potassium bicarbonate in 200 milliliters Example 6 .-21 -Iodo-1 7a-Hydr0xy-4,9 (11 -Pregnadien- 3,20-Di0ne (IIIb) A mixture containing 28.2 grams of l7a,21-dihydroxy- 4,9(11)-pregnadien-3,20-dione and 300 milliliters of pyridine was cooled in an ice bath. Twenty milliliters of methanesulfonyl chloride was added with stirring to produce a homogeneous reaction mixture. The mixture was cooled for three hours then slowly diluted with one liter of water, which resulted in the precipitation of 17u,21- dihydroxy-4,9(l1)-pregnadien-3,20-dione 21-methanesulfonate (IIb). The product was filtered, washed with water and dried to give 30.4 grams.

29 grams of the above methanesulfonate was dissolved in 408 milliliters of acetone and thirty grams of sodium iodide in 258 milliliters of acetone was added. The resulting mixture was warmed under reflux for a period of fifteen minutes with stirring. a solution of three grams of sodium thiosulfate in 780 milliliters of water were added. A precipitate formed which was filtered and dried to yield 27.5 grams of 21- iodo 17a hydroxy 4,9(11) pregnadien 3,20 dione (IIIb) with a melting point of to degrees centigrade (decomposition).

Example 7.21 Fluoro 17a Hydroxy 4,9(11)- Pregnadien-3,20-Di0ne (I Vb) 26.5 grams of 21-iodo-l7a-hydroxy-4,9(ll)-pregnadien-3,20-dione, dissolved in 2000 milliliters of acetonitrile, was warmed to forty degrees centigrade while being shielded from daylight. Three portions of seventeen milliliters each of a fifty percent aqueous silver fluoride solution were added at thirty minute intervals. The reaction mixture was warmed at forty degrees centigrade for an' additional two hours and then filtered through Celite (diatomaceous filter aid). The filtrate was concentrated to a volume of milliliters, 600 milliliters of water was added and the resulting mixture extracted with three 300 milliliter portions of methylene chloride. The pooled extracts were washed with water, dried over sodium sulfate and concentrated to dryness. The dry residue weighed eighteen grams and was dissolved in 500 milliliters of methylene chloride. This was poured onto a 500 gram column of Florisil and eluted with 1000 milliliter fractions, as follows:

Fractions lto 3 AcetonezSkellysolveBhexanes::9:9l.

Fractions 4 to 7 AcetonezSkellysolve B: :10:90. Fractions 8 to 11 AcctonezSkellysolve B: :12:88. Fractions 12 to 15 AcetonezSkellysolve B: 13:87. Fractions 16 to 32 AcetonezSkellysolve B: 15:85.

300 grams of ice and 7 to give 08 gram of 17a,2l-epoxy-4,9(11)-pregnadien- 3,20-dione with a melting point of 183 to 192 degrees centigrade. The infrared absorption spectrum indicated the absence of a hydroxyl group.

This substance is a valuable diuretic agent and regulator of mineral metabolism and is accordingly useful in treating edema, and circulatory and cardiac conditions. It also exhibits gonadotropin inhibiting and central nervous system regulating activity.

Example 8.21 Fluoro 17a Acetoxy 4,9(11)- Pregnadiene 3,20 Dione (Vb) 21 Fluoro 3,17a Diacetxy-3,5,9(Z1 -Pregnalrien-20-One (VI b) A solution containing 1.5 grams of 21-fiuoro-17a-hydroxy-4,9(11)-pregnadiene-3,20-dione, 1.5 grams of paratoluenesulfonic acid monohydrate, ten milliliters of acetic anhydride and 45 milliliters of acetic acid was allowed to stand for a period of sixteen hours at 25 degrees centigrade. The excess anhydride was hydrolyzed by adding 300 milliliters of ice water While stirring and cooling. After one hour the reaction mixture was filtered and the precipitate washed with water and dried to give 1.4 grams of dry product. The dry residue was dissolved in fifteen milliliters of methylene chloride, fifteen milliliters of Skellysolve B was added and the solution adsorbed on a column of sixty grams of Florisil. The column was eluted with seventy milliliter portions of a mixture composed of ten percent of acetone and ninety percent of Skellysolve B hexanes.

Fractions 3 and 4 weighed 0.312 gram. The pooled product was dissolved in two milliliters of methylene chloride and 2.5 milliliters of Skellysolve B hexanes, concentrated and cooled to yield 240 milligrams of crystalline 21 fiuoro 3, 17oz diacetoxy 3,5,9(11) pregnatrien-ZO-one (VIb), with a melting point of 182 to 185 degrees centigrade.

Analysis.-Calculated for C H FO C, 69.74; H, 7.26. Found: C, 70.20; H, 7.38.

Fractions 6 to 10 weighed 0.90 gram and were pooled and crystallized from methylene chloride-Skellysolve B hexanes to give 0.77 gram of 21-fluoro-l7a-acetoxy- 4,9(11)'-pregnadiene-3,20-dione (Vb), with a melting point of 218 to 220 degrees centigrade.

The infrared absorption spectrum showed the following maxima: 1717 centimeterv (C=O of ester and ketone), 1662 centimeters- (conjugated ketone), 1610 centimeters (conjugated C=C).

Analysis.-Calculated for C H FO F, 4.89. Found: F, 5.02.

21 fiuoro 17a hydroxy 4,9(11) pregnadiene- 3,20-dione is converted to other 21-fiuoro-17a-acyloxy- 4,9(11) pregnadiene 3,20-diones and 21 fiuoro- 3,17a-diacyloxy-3,5,9(1l)-pregnatrien-20-ones by esterification ,of the 17a-hydroxyl and enol esterification of the 3-ketone by reaction with the appropriate acid, acid anhydride or acid halide, in the presence of an acid catalyst such as paratoluenesulfonic acid or trifluoroacetic anhydride. In the same manner as in Example 8 but instead of employing acetic anhydride, the substi tution of such acid anhydrides as propionic, butyric, isobutyric, valeric, enanthic, caproic, caprylic, benzoic, cyclopentylpropionic, phenylacetic, phenylpropionic, trimethylacetic, t-butylacetic, cyclopentylcarboxylic, ethylbutyric, o-toluic, dodecanoic or cyclohexylacetic is productive of 21-fluoro-17a-propionyloxy-4,9 1 1 -pregnadiene- 3,20-dione,

21-fluoro-3, 17 ot-dipropionyloxy-3,5 ,9 1 1 )'-pregnatrien- 20-one,

21-fluoro-17ot-butyryloxy-4,9( 1 1) -pregnadiene-3,20-

dione,

2 1-fluoro-3 17a-dibutyryloxy-3,5 ,9 l1)-pregnatrien- 20-one,

2l-fiuoro-17a-isobutyryloxy-4,9( 11 )-pregnadiene-3,20-

dione,

21-fiuoro-3,17a-diisobutyryl-oxy-3,5,9 1 1 -pregnatrien- 20-one,

21-fluoro-17a-valeryloxy-4,9( 11)-pregnadiene-3,20-

dione 21-fluoro-3,17a-divaleryloxy-3,5,9(11)rpregnatrien- 20-one,

21-fiuoro-17a-enanthoyloxy-4,9( 11)-pregnadiene-3 ,20-

dione,

21-fluoro-3,17a-dienanthoyloxy-3,5,9( 1 1 -pregnatrien- ZO-one, 21-fluoro-17a-caproyloxy-4,9( 1 l -pregnadiene-3,20-

dione, 21-fluoro-3,17a-dicaproyloxy-3,5,9(11)-pregnatrien- 20-one,

21-fluoro-17a-capry1oxy-4,9(11)-pregnadiene-3,20-

dione,

2l-fluoro-3,17a-dicapryloxy-3 ,5 ,9 1 1 -pregnatrien- 20-one,

21-fiuoro-17a-benzoy1oxy-4,9 11)-pregnadiene-3,20-

dione,

21-fluoro-3,17a-dibenzoy1oxy-3,5,9 1 1)-pregnatrien- 20-one,

21-fluoro-17a-cyclopentylpropionyloXy-4,9 1 1) pregnadiene3,20-dione,

21-fiuoro-3 ,17a-dicyclopentylpropionyloxy-3,5,9( 1 1)- pregnatrien-ZO-one,

2l-fiuoro-17a-phenylacetoxy-4,9(11)-pregnadiene- 3 ,20-dio-ne, 21-fluoro-3, 17a-diphenylacetoxy-3,5,9(11)-pregnatrien- 20-one, 21-fluoro-17a-phenylpropiony1oxy-4,9( l 1 -pregnadiene- 3 ,20-dione, 2l-fluoro-3,17ot-diphenylpropionyloxy-3,5,9(11)- pregnatrien-ZO-one, 21-fluoro-17a-trimethylacetoXy-4,9 1 1 -pregnadiene- 3 ,20-dione,

2 1-fluoro-3, 17a-ditrimethylacetoxy-3,5 ,9 11)-pregnatrien-ZO-one,

21-fiuoro-17a-t-butylacetoxy-4,9 1 1 -pregnadiene- 3,20-dione,

21-fluoro-3,l7u-di-t-butylacetoxy-3,5,9(11)-pregnatrien- 20-one,

21-fluoro-17a-cyclopentylcarboxyloxy-4,9(11)- pregnadiene-3,20-di0ne,

21-fiuoro-3,17ix-dicyclopentylcarb0xyloxy-3,5,9(11)- pregnatrin-ZO-one,

21-fluoro-17oc-ethylbutyryloxy-4,9(11)-pregnadiene 3,20-dione,

21-fluoro-3,17a-diethy1butyryloxy-3,5,9( 1 1)-pregnat1ien- 20-one, v 21-fluoro-17oco-toluyloxy-4,9(11)-pregnadiene-3,20-

dione, 21-fluoro-3,17a-di-o-toluyloxy-3,5,9(11)-pregnatrien- 20-one,

21 -fiuoro- 17a-decanoyloxy-4,9 1 1 )-pregnadiene-3,20-

dione,

2 1-fluoro-3, 17a-didecanoyloXy-3,5 ,9 1 1 )-pregnatrien- 20-one,

21-fluoro-17ot-cyclohexylacetoxy-4,9 1 1 -pregnadiene- 3 ,20-dione, and 21-fluoro-3,17a-dicyclohexylacetoxy-3,5,9(11)-pregnatrien-ZO-one, V respectively.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art to which this invention pertains, and the invention is therefore to be limited only by the scope of the v appended claims.

9 We claim: 1. 21-fluoro-3,17a-disubstituted steroids of the following formula:

5 trien-ZO-one.

wherein Ac is an acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms,

inclusive.

2. 21 fluoro 3,170: diacetoxy 3,5(9)11-pregna- References Cited in the file of this patent UNITED STATES PATENTS 

1. 21-FLUORO-3,17A-DISUBSTITUTED STEROIDS OF THE FOLLOWING FORMULA: 